# Development and Mechanistic Studies of an Engineered Human Enzyme to Abrogate Immune Suppression due to Elevated Methylthioadenosine (MTA) by MTAP null/low Tumors

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2021 · $378,348

## Abstract

Development and Mechanistic Studies of an Engineered Human Therapeutic to Abrogate
Immune Suppression due to Elevated Methylthioadenosine (MTA) by MTAP null/low Tumors
One of the most common lesions observed across a broad number of cancers is the homozygous genetic
deletion of methylthioadenosine phosporylase (MTAP), an enzyme that normally functions in amino acid and
nucleotide recycling pathways. Deletion of MTAP in tumors results in the accumulation and secretion of its
substrate methylthioadenosine (MTA). It is established that MTA is a very potent immunosuppressive molecule;
importantly in preliminary studies our lab obtained strong in vivo evidence from multiple murine tumor models
that the production of MTA by MTAPnull/low tumors strongly attenuates anti-tumor immune responses. This
proposal describes an interdisciplinary team effort at the University of Texas at Austin detailing the development
of a novel biologic cancer therapeutic, to reverse the immunosuppressive effects of MTA and aid in the treatment
of patients with MTAPnull/low tumors as a key biomarker. In preliminary studies we have demonstrated that
administration of an engineered human MTA degrading therapeutic (based on the human MTAP) can reverse
the deleterious effects of MTA on lymphocytes in vitro, drastically retards the growth or elicits complete
remissions of MTAP null murine cancer allografts and restores populations of T cells in both the tumor and tumor
draining lymph node (TDLN) and demonstrates additive/synergistic effects when used in combination with
existing immune checkpoint inhibitors.
The evidence that the consequence of MTAP deletion acts to suppress immune effector cells and promote
tolerogenic stromal cell phenotypes through the buildup of MTA now suggests a clear mechanism for why this is
one of the more common gene deletions observed in cancer. Overall, we hypothesize that MTAP deletions in
cancers act as an immune checkpoint that can be reversed therapeutically by enzymatic degradation of MTA in
the tumor microenvironment using an engineered human methylthioadenosine phosphorylase. The work
proposed here will seek to: (i) elucidate the cellular immunology and the biochemical/metabolomic and signaling
mechanism(s) through which elevated extracellular MTA suppresses immune function; (ii) help clarify how MTA-
mediated methyltransferase inhibition and remodeling of metabolism together with (likely secondarily) activation
of the purinergic receptors impact lymphocytes; (iii) examine the efficacy of combinatorial treatments using
standard of care antibody immune checkpoint inhibitors and very importantly (iv) develop an optimized MTA
degrading drug that has the requisite pharmacological properties for late/stage preclinical/clinical administration..

## Key facts

- **NIH application ID:** 10188468
- **Project number:** 5R01CA240700-03
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Everett Stone
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $378,348
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10188468

## Citation

> US National Institutes of Health, RePORTER application 10188468, Development and Mechanistic Studies of an Engineered Human Enzyme to Abrogate Immune Suppression due to Elevated Methylthioadenosine (MTA) by MTAP null/low Tumors (5R01CA240700-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10188468. Licensed CC0.

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